Genetic Variant USB1:p.Ser2Arg (chr16-58001489-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024598.4(USB1):c.6C>G(p.Ser2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

USB1
NM_024598.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.57

Publications

1 publications found

Variant links:

Genes affected

USB1 (HGNC:25792): (U6 snRNA biogenesis phosphodiesterase 1) This gene encodes a protein with several conserved domains, however, its exact function is not known. Mutations in this gene are associated with poikiloderma with neutropenia (PN), which shows phenotypic overlap with Rothmund-Thomson syndrome (RTS) caused by mutations in the RECQL4 gene. It is believed that this gene product interacts with RECQL4 protein via SMAD4 proteins, explaining the partial clinical overlap between PN and RTS. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]

USB1 Gene-Disease associations (from GenCC):

poikiloderma with neutropenia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1269682).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024598.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USB1	NM_024598.4	MANE Select	c.6C>G	p.Ser2Arg	missense	Exon 1 of 7	NP_078874.2
USB1	NM_001195302.2		c.6C>G	p.Ser2Arg	missense	Exon 1 of 6	NP_001182231.1	Q9BQ65-2
USB1	NM_001204911.2		c.6C>G	p.Ser2Arg	missense	Exon 1 of 4	NP_001191840.1	Q9BQ65-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USB1	ENST00000219281.8	TSL:1 MANE Select	c.6C>G	p.Ser2Arg	missense	Exon 1 of 7	ENSP00000219281.3	Q9BQ65-1
USB1	ENST00000539737.6	TSL:2	c.6C>G	p.Ser2Arg	missense	Exon 1 of 6	ENSP00000446143.2	Q9BQ65-2
USB1	ENST00000896281.1		c.6C>G	p.Ser2Arg	missense	Exon 1 of 6	ENSP00000566340.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0077

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

-1.6

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.0

REVEL

Benign

0.042

Sift

Uncertain

0.012

Sift4G

Benign

0.12

Polyphen

0.021

Vest4

0.12

MutPred

0.24

Gain of MoRF binding (P = 0.0055)

MVP

0.030

MPC

0.34

ClinPred

0.43

GERP RS

-5.2

PromoterAI

-0.24

Neutral

(source)

Varity_R

0.28

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over